Carbapenem Resistance in Asia – Systemic Causes

I had some time to reflect after finishing a rather interesting meeting in Thailand organised by a pharmaceutical company. In their usual way, the company had invited representatives from different countries in the region to obtain perspectives on the issue of antimicrobial resistance – specifically carbapenem resistance and carbapenem-resistant Enterobacteriaceae (CRE) – in our countries. Naturally, they were interested in finding an angle to position their product, but the ensuing discussion was nonetheless fascinating. There were participants from India, China, Taiwan, Hong Kong, Japan, Thailand, Malaysia, Pakistan, Philippines, Vietnam, and Indonesia, along with an expert co-chair for the meeting from Spain.

It is sobering to note that every country – even Japan – has CRE. Japan has relatively few issues with antimicrobial resistance compared to most countries in Asia, and their surveillance system for infectious diseases is first rate. I had the chance to look up the Japanese data on CRE, and thankfully most of it is summarised on on their National Institute of Infectious Diseases website. Approximately half of their CRE’s are due to production of ampC enzymes coupled with porin changes, which are not relevant with regards to transmissibility, while the carbapenemase produced by virtually all the other CRE’s is IMP. Again, not a gene with epidemic potential such as NDM, KPC or even OXA. Less than 1% of Japan’s Enterobacteriaceae are CRE. It is noteworthy that their rate of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is somewhere between 5% and 10%, which is one of the lowest in the world.

Not unexpectedly, CRE rates are high in Indian and Pakistani hospitals, somewhere in the region between 20% and 40%. Their ESBL rates are close to 80% for healthcare-associated infections, and also fairly high in community-associated infections in patients who had not previously been hospitalised. Although most of the country representatives reported problems with the control and treatment of infections caused by Acinetobacter baumannii(some isolates were reportedly resistant to all available antibiotics), it is clear that the number of CRE infections is increasing even in surrounding countries such as Malaysia, Indonesia, Thailand, Vietnam, and China. Again, Japan is the odd one out – so far.

Why does Japan not have high Gram-negative antimicrobial resistance rates like other countries in the region? The Japanese representative shared that following the outcry over the rise of MRSA infections in the 1990s and 2000s, concerned physicians acted and started prescribing less (and less broad-spectrum) antibiotics. Personally, I believe there are other contributory reasons that may be important. Japan is geographically isolated, and their medical tourism industry has not really taken off. A significant proportion of their food supply is still produced domestically. Although there is no regulatory restriction of antibiotics as growth promoters in Japan, the majority of these are ionophores and polypeptides, which have no equivalent in human antibiotics. Their health system is also very advanced, with sufficient well-trained clinical microbiologists and infectious diseases physicians. Or perhaps they have just been fortunate, who knows?

In varying degrees, however, many of the other countries reported systemic issues that both promote and complicate the control of antimicrobial resistance, even carbapenem resistance. These include:

Crowded facilities and hospitals with high turnover rates – resulting in a lack of isolation resources or even cohorting resources for patients with transmissible diseases.

Lack of awareness or under-promotion of infection control, including proper environmental cleaning. Many hospitals (even local ones!) do not take this seriously with regards to stopping the transmission of antimicrobial resistance. Of course, if the facilities are crowded (1. above), then infection control becomes at best challenging and at worst impossible.

Lack of trained ID physicians. This was particularly apparent in Indonesia, India and Pakistan. Now, it is not true that all ID physicians are conservative and judicious with respect to antibiotic prescription (in fact, if one was to be honest, some of “our kind” are probably serial antibiotic abusers). However, the lack of proper training in antibiotic prescription and lack of appreciation of the issue of antimicrobial resistance has resulted in excessive and often inappropriate use of antibiotics in many hospitals in the region.

Lack of stringent antibiotic control policies or antimicrobial stewardship programs. This exacerbates the problem of inappropriate antimicrobial prescribing as described above, particularly in countries where there are multiple different generics (one person described how there were thirteen carbapenems available for prescribed at that person’s institution). As we have also discovered in Singapore, it is hard to turn back the clock. Physicians and surgeons used to autonomy and unchecked antibiotic prescription are often resistant – perhaps justifiably – to efforts to limit that autonomy. Compare this situation to countries (i.e. Australia, New Zealand, Scandinavian countries, Holland, etc.) where antibiotic prescription is more prudent: physicians from these countries are often surprised to find that broad-spectrum antibiotics can be so freely prescribed in the region.

It is clear that there is not a one-size-fits-all solution. Adopting infection control guidelines from U.S. or Europe (or Singapore for that matter) is not going to work in parts of the world where resources are severely limited. It is also clear that significant government awareness of the problem of antimicrobial resistance, and commitment to development of the healthcare structure and facilities is required to tackle this problem in many regional countries. How to make this happen will probably be unique to each country or region. The Chennai Declaration gave many of us a sense of hope, but it remains to be seen how much of that will be translated into policy, and how much of that again is implemented. But it is also hopeful that there are more and more healthcare professionals who are cognizant of this problem, and who are actively working in their own institutions and countries to change the existing culture.